Quaternary halides of certain tropane alkaloids



United States Patent 1 2,903,394 QUATERNARY HALIDES OF CERTAIN TROPANEALKALOIDS Robert Goodman Johnston and Kenneth Eric Vincent Spencer,Edinburgh, Scotland, assignors to T. & H.

Smith Limited, Edinburgh, Scotland, a British com- No Drawing.Application April 12, 1957 Serial No. 652,374 Claims priority,application Great Britain May .1, 1956 14 Claims. (Cl. 167-58) Thepresent invention concerns improvements in and relating to quaternarysalts and solutions thereof. It is particularly concerned with novelquaternary salts of tropine esters and pseudo-tropine esters and withtheir preparation and use as hypotcnsive agents.

It is often most desirable in surgical operations to produce controlledhypotension. This can be done by the intravenous infusion of substanceswhich are termed hypotensive agents, one example of which ishexamethonium dibromide.

It is an object of the present invention to produce new quaternary saltshaving hypotensive activity.

It is another object of the invention to produce solutions which can beadministered to patients by intravenous infusion in order to reduceblood pressure during surgical operations.

It is a further object to provide quaternary salts of tropine esters andpseudo-tropine esters which have valuable therapeutic properties.

With these and other objects in view the present invention providesquaternary salts of esters selected from the group consisting of tropineesters and pseudo-tropine esters, said quaternary salts having thegeneral formula:

r'- ea d COOCHzN-OH; Ho-o Y X H, --oH---ort, 17. wherein:

X represents the anion of an acid, especially an inorganic acid,

It represents the valency of the anion X,

Y represents an organic carboxylic acyl group, and

Q represents the non-metallic atoms necessary to complete a heterocyclicradical, especially an unsubstituted S-membered heterocyclic radical ofthe general formula C H D (wherein D represents a divalent memberselected from the group consisting of -S, 0-- and -NH-).

These quaternary salts may be termed heterocyclomethyl acyltropiniumsalts and heterocycloylrnethyl acylpseudo-tropinium salts, respectively.The term heterocycloylmethy is used to designate the group (.2 :OOO-CH2The process of the present invention comprises preparing a quaternaryhalide of an ester selected from the group consisting of tropine estersand pseudo-tropine esters by reacting an organic carboxylic ester oftropine or of pseudo-tropine with a heterocycloylmethyl halide of thegeneral formula:

Ci b co-cn.-x

wherein Q and X have the values given above, preferably in an inertsolvent, and preferably with the aid of heat. The reaction takes placeon leaving the reactants in contact with one another and heat is notessential, although it accelerates the reaction. The presence of adiluent is not essential although it facilitates the produc: tion of thequaternary halide.

From the resulting quaternary halides, preferably the chlorides,quaternary salts of other acids can be made. A number of general methodsare available for this, three of which are as follows:

(a) Double decomposition of an aqueous Or aqueous alcoholic solution ofa quaternary chloride with a soluble alkali metal salt such as sodiumbromide or iodide.

b) Metathesis of a quaternary halide with, for example, a silver salt,preferably in alcohol.

('c) Reaction of an alcoholic solution of a quaternary halide with anacid in presence of an organic epoxide. This method is described by O.Sackur in Bull. Soc. Chim., 1952, 796.

The quaternary salts of the present invention have useful therapeuticproperties. When injected into the human blood stream they exhibit to avery useful degree the power to block transmission of nervous impulsesacross sympathetic ganglia and cause a fall in blood pressure. Some atleast of the quaternary salts, especially Z-thenoylmethyl homatropiniumbromide, 2-thenoylmethyl phenylacetyltropinium bromide and2-furoylmethyl phenylacetyltropinium bromide, exhibit a hypotensiveaction which exceeds that of hexamethonium dibromide, and are inaddition of low toxicity. The duration of action is much less than thatof hexamethonium dibromide. The hypotension produced can readily beantagonised, when required, by adrenaline or methedrine. The quaternarysalts are thus useful for producing controlled hypotension, for exampleduring surgical operations. Their hypotensive potency can be compared bymeasuring the reduction in the extent of contraction of the nictitatingmembrane of the cat in response to the stimulation of the preganglionicfibres of the cervical sympathetic vnerve.

The heterocycloylmethyl quaternary salts of pseudotropine carboxylicesters appear, in general, to have a lower hypotensive potency than thecorresponding hetero-v cycloylmethyl quaternary salts of tropinecarboxylic esters. Nevertheless, many of them have a very useful potencywhen measured in the above way. The relative potencies of twelve typicalheterocycloylmethyl quaternary salts, some derived from tropine estersand the others from pseudo-tropine esters, were as follows:

dibromide was 10.

The heterocycloylmethyl quaternary salts of tropine carboxylic estersand of pseudo-tropine carboxylic esters are thus useful for producingcontrolled hypotension, for example during surgical operations.

J As regards the preferred quaternary salts, the chlorides, bromides andiodides, the potencies of these three salts of the same tropine orpseudo-tropine carboxylic esters are the same, but their solubility inwater is very different. The chlorides are the most soluble and theiodides the least. The chlorides are therefore generally more convenientfor use as hypotensive agents in surgical operations.

In making the heterocycloylmethyl acyltropinium andacyl-pseudo-tropinium halides, it is preferred to use inert solvents ofa polar nature such as ketones. The halides referred to are highlyreactive and it is not therefore essential to heat the reaction mixture,as a good yield may be obtained by allowing the mixture to stand for asufficient period of time at room temperature. It is preferred, however,to heat the reactants as the formation of quaternary salts is thenrapid.

The invention will be illustrated by, but is not limited to, thefollowing examples.

' Example 1.2-tlzen0ylmethyl homatrapinium bromide "5.0 gms. (0.0182 M)of homatropine were dissolved, with gentle warming, in 40 mls. of dryacetone. 25 mls. of a solution of 2-bromacetylthiophene (5.14 gms. 0.025M) in acetone were added all at once, and the reaction mixture wasallowed to stand 24 hours at room temperature. By this time aconsiderable amount of pale-tan solid had precipitated. After refluxingfor 2 hours, the solid was filtered, ground under acetone, filtered anddried, giving 8.0 gms. (91%) of material, M.P. 190-193". Tworecrystallisations from acetone containing a small amount of isopropanolafforded 5.36 gms. (61%) of the salt, M.P. 197198, not changing onfurther recrystallisation and containing 16.59% bromide as compared tothe theoretical figure of 16.69%.

. Example 2.--2-fur0ylmethyl homatropinium chloride Homatropine (20.0gm.) and 2-chloroacetylfuran (11.6 gm.; 10% excess) were dissolved in200 mls. dry acetone and allowed to stand in the dark at roomtemperature. After two days a syrupy lower layer had formed. 5 hoursreflux on the steam bathresulted in production of a dark brown resin,which, after decanting the acetone layer and refluxing with dry benzenegave a brown power (26.3 gm.) of low and indefinite M.P. (about 90 C.).This was repeatedly charcoaled in alcoholic solution and reprecipitatedwith ethyl acetate. This treatment gave a creamy-white solid which couldnow be recrystallised from ethanol and ethyl acetate. In this way 16.2gm. (51%) white crystals were obtained, M.P. 1878 C. The chlorinecontent was 8.45% as compared with a theoretical value of 8.26%.

I Example 3.2-pyrr0ylmethyl homatropinium chloride Homatropine (5.50gm.) and 2-chloroacetylpyrrole (2.73 gm.; excess) were refluxed threehours in 70 ml. acetone. Most of the acetone was removed in vacuo andreplaced by dry benzene. The dark-brown precipitate so obtained (7.0gm.) could not be recrystallised and was extracted with dry acetone in aSoxhlet apparatus, whereby 3.3 gm. greyish solid was obtained. Aftercharcoaling in alcohol solution, recovery of the solid, and twocrystallisations from methanol and ethyl acetate 1.75 gm. (21%) whitepowder was obtained, M.P. 224-5 C. dec.; chlorine content 8.49% ascompared with the llQOretical value of 8.61%. 0'

4 Example 4.2 thenoylmethylbenzoyl-pseudo-tropinium bromideBenzoyl-pseudo-tropine (4.90 gm., 0.02 M) and 2 bromacetylthiophene(4.50 gm., 0.022 M) were refluxed 5 hours in 50 ml. dry acetone. Oncooling and filtering 8.1 gm. (91%) cream coloured solid was collected,M.P. 2l4-216 C. After recrystallisation from aqueous alcohol, washingwith acetone and drying at C. in vacuo the yield of pure material was5.6 gm. (62%), M.P. 223-4 C. Assay by determination of bromine indicateda purity of over 99%.

By substitution of other esters of pseudo-tropine for thebenzoyl-pseudo-tropine mentioned in the above example, the followingwere obtained:

2 thenoylmethylphenylacetyl pseudo tropinium bromide'M.P. 185-6" 0. ,7

2 thenoylmethylisobutyryl-pseudo tropinium bromide M.P. 193-4" C.

Example 5.--2-pyrroylmethyl phenylacetyl-pseudotropinium bromidePhenylacetyl-pseudo-tropine (2.60 gm., 0.01 M) and 2-chloroacetylpyrrole (1.30 gm., 0.01 M) were refluxed 4 hours in 10 mls.dry acetone. On cooling no solid separated. The crude quaternary wastherefore poured into excess ether and the greyish solid thus obtainedwas charcoaled in 10% aqueous solution. After filtration a concentratedsolution of potassium bromide was added, producing a white precipitateof the quaternary bromide, M.P. 181-2 C., not altering on furthercrystallisation and having a bromine content of 18.12% against thecalculated figure of 17.90%.

Example 6.2-furoylmethyl phenylacetyl-pseudotropim'um bromidePhenylacetyl-pseudo-tropine (11.5 gm.) and 2-bromacetylfuran (9.2 gm.,10% excess) were refluxed two hours in ml. of methylethylketone. Oncooling, the amount of crude material collected was 15.1 gm. (76%yield). This, after crystallisation from ethanol/ethylacetate weighed13.5 gm. (68%), M.P. -1" C., and had a bromine content of 17.24% ascompared with the theoretical figure of 17.32%.

It is convenient to employ the quaternary salts of the present inventionas hypotensive agents in the form of simple aqueous solutions. It isdesirable that these solutions should be kept out of strong daylight;for example they should be contained in amber coloured ampoules andpreferably stored in the dark. The quaternary salts are convenientlysupplied in ampoules containing a 5% weight by volume solution. This isintended to be diluted twenty to one hundred times for use in controlledintravenous infusion. The 5% solution is sensitiveto direct sunlight,decomposition occurring with formation of a deposit. It is stable in thedark and does not readily decompose in diffused daylight.

' In using the quaternary salts for reduction of blood pressure during asurgicaloperation, an aqueous solution containing from 0.5 to 2.5 mg.per ml. may be administered as an intravenous drip. Hypotension can beachieved in a space of two to ten minutes depending on the rate ofadministration. The desired degree of hypotension can be maintained forprolonged periods by continued administration at a slow rate andrecovery is rapid. Operations can be carried out using total quantitiesvarying from 50-500 mgms. The action can readily be reversed by theadministration of, for example, methedrine,

Hal

wherein Hal represents a halogen atom, Y represents the acyl radical ofan organic carboxylic acid selected from the group consisting ofmandelic, phenylacetic, benzoic, tropic and isobutyric acids, and Drepresents a divalent member selected from the group consisting of S-,-O and -NH.

2. 2-thenoylmethyl homatropinium halide salt.

3. 2-furoylmethyl homatropinium halide salt.

4. 2-pyrroylmethyl homatropinium halide salt.

5. Z-thenoylmethyl benzoyl pseudo tropinium halide salt.

6. 2-ther1oylmethyl homatropinium bromide.

7. Z-thenoylmethyl phenylacetyl-tropim'um bromide.

8. A liquid for intravenous injection to produce hypo tension consistingessentially of a solution in water of 0.5 to 2.5 mgms. per ml. of2-thenoylmethyl homatropinium bromide.

9. The process of preparing a quaternary halide which comprises reactinga heterocycloylmethyl halide of the general formula:

-0 O-0 H Hal wherein D represents a member selected from the group 6consisting of S, O- and -NH-, and Hal represents a halogen atom, with anester of the general formula:

wherein Y represents the acyl radical of an organic carboxylic acidselected from the group consisting of mandelic, phenylacetic, benzoic,tropic and isobutyric acids.

10. The process as claimed in claim 9 wherein the organic carboxylicester is homatropine.

11. The process as claimed in claim 9 carried out in presence of aninert solvent for the reagents.

12. The process as claimed in claim 9 carried out in the presence of apolar solvent.

13. The process as claimed in claim 9 carried out in presence of aketone as polar solvent.

14. The process as claimed in claim 9 in which heating is employed.

References Cited in the file of this patent UNITED STATES PATENTS2,828,312 Johnston et a1. May 25, 1958

1. A QUATERNARY HALIDE OF THE GENERAL FORMULA:
 8. A LIQUID FORINTRAVENOUS INJECTION TO PRODUCE HYPOTENSION CONSISTING ESSENTIALLY OF ASOLUTION IN WATER OF 0.5 TO 2.5 MGMS. PER ML. OF 2-THENOYLMETHYLHOMATROPINIUM BROMIDE.